We continue to improve our understanding of the pathogenesis of pre-malignant monoclonal gammopathy of undetermined significance(MGUS) and multiple myeloma (MM), as summarized below. First, in a recent study we have determined that 27 of 30 MM tumors were preceded by an MGUS tumor, providing some of the first evidence that de novo MM is infrequent. Significantly, in four (13%) of these patients, the MM and preceding MGUS tumors were light chain only, confirming that light chain only MGUS is a significant clinical entity, and suggesting that light chain only MM usually is preceded by light chain only MGUS and not MGUS that stops synthesis of IgH chains. Second, we have identified seven primary translocation partners that are present in 40% of multiple myeloma tumors and comprise three translocation groups: CYCLIN D, MAF, and MMSET/FGFR3. Third, we determined that the dysregulation of a CYCLIN D gene is an early and unifying event in MGUS and multiple myeloma. Fourth, these two early oncogenic events enabled us to propose the TC (translocation/cyclin D) classification, which appears to be applicable to all MGUS and multiple myeloma tumors, but also has been demonstrated to have significance for therapeutic decisions. Fifth, we have determined that secondary translocations, which are involved in tumor progression, have structural features and chromosomal partners that distinguish them from primary translocations. Sixth, we have determined that NFKB activation either by extrinsic ligands or by mutations in at least nine components of the NFKB pathways is important for the survival and growth of normal plasma cells as well as most MGUS and MM tumors. This suggests that MGUS and MM tumors may be addicted to this pathway, and thus sensitive to drugs that inhibit the NFKB pathway. Seventh, we have identified a RAS paradox, i.e., N-RAS mutations are much more prevalent in tumors that express CYCLIN D1 (22%) than in tumors that express CYCLIN D2 (4%), whereas K-RAS mutations have the same prevalence (17%) in both kinds of tumors. Although we presently do not understand this RAS paradox, it seems significant that N-RAS mutations were identified in 3 of 39 (6%) MGUS tumors, but K-RAS mutations were identified in none of the 39 MGUS tumors. It seems that K- and N-RAS are not interchangeable but actually have different roles in the pathogenesis of MM, a result that is consistent with recent reports by others that K- and N-RAS are not functionally equivalent. Eighth, we have determine that the PI3K/AKT pathway is activated in at least 20% of MM tumors, usually by overexpression of DEPTOR induced by MAF and yet to be identified mechanisms, and less often by inactivation of PTEN. Finally, inactivation or mutation of p53, MYC rearrangements and dysregulation, and additional disruption (beyond the early dysregulation of a CYCLIN D gene) of the RB pathway appear to be relatively late progression events that are associated with increased proliferation and a poor prognosis. The RB pathway alterations are manifested by homozygous deletion of p18INK4c (10-30% of proliferative tumors and cell lines) vs an increase in the expression of p18 (60% of cell lines and proliferative tumors);this increase probably results from the fact that E2F enhances transcription of genes that increase proliferation, but also of p18. The insensitivity of the RB pathway to the inhibitory effects of p18 remains unexplained except for a small fraction of tumors that have inactivated RB1.